Abstract
Epstein–Barr virus (EBV)-associated smooth muscle tumours (SMT) have been reported in young patients with induced immunosuppression associated with organ transplantation, acquired immunodeficiency syndrome or congenital immunodeficiencies. EBV-associated SMT are frequently multicentric or multifocal and often occur in unusual locations. We are reporting a case of EBV-associated multicentric SMT that occurred after kidney transplantation in a 2-year-old boy with a history of oligomeganephrony. Headaches and left VIth cranial nerve paralysis led to the discovery of a brain tumour 3 years after transplantation. There were multiple pulmonary, hepatic and splenic nodules and enlarged mesenteric lymph nodes. Histological examination revealed multicentric SMT of uncertain malignant potential. Further investigations using in situ hybridisation demonstrated EBV early RNAs in the nucleus of most tumour cells. The immunosuppressive therapy was reduced, and the child was treated with chemotherapy, but died 2 months later, due to neurological complications.
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Introduction
Leiomyosarcomas are very rare in the paediatric age group [13]. In children with acquired immunodeficiency syndrome (AIDS) or induced immunosuppression following transplantation, the incidence of apparently benign or malignant spindle-cell (usually smooth-muscle) tumours is higher than expected for this age group [3, 9, 20]. Epstein–Barr virus (EBV)-associated smooth muscle tumours (SMT) are uncommon, distinctive mesenchymal tumours found in immunocompromised patients, including children, with AIDS [16], induced immunosuppression following transplantation [15], severe congenital immunodeficiency [12, 17, 28] or ataxia–telangiectasia [22]. The intracranial location of EBV-associated SMT in immunocompromised patients is extremely rare [12].
In this report, we are presenting a case of EBV-associated multicentric SMT that occurred after kidney transplantation in a child. Tumours were located in the brain, lungs, liver, spleen and mesenteric lymph nodes.
Clinical history
At birth, the boy was premature, with bilateral renal hypoplasia related to oligomeganephrony and renal insufficiency necessitating haemodialysis from the age of 15 months. Kidney transplantation was performed at 2 years of age. The recipient was EBV-seronegative and the donor seropositive. EBV primary infection was detected within 6 months of the renal transplant. Post-transplant immunosuppressive therapy included anti-lymphocyte globulin (days 1–10 post-transplantation); methylprednisolone (2 mg/kg per day on days 1–10, then progressively reduced to 0.35 mg/kg per day at 6 months) and cyclosporin (from day 8, 5 mg/kg). Azathioprine was given initially, but the patient was switched to mycophenolate mofetil (600 mg/m2) at day 5 because of severe leukopenia. Long-term treatment included cyclosporin (7 mg/kg per day), prednisone (0.35 mg/kg per day) and mycophenolate mofetil (400 mg/m2). The patient was admitted to hospital with headaches and left VIth cranial nerve paralysis 3 years after transplantation. Physical examination revealed hepatomegaly and splenomegaly. A cerebral computed tomography (CT) scan demonstrated a right temporal mass, measuring 5 cm, that was displacing the brain stem (Fig. 1). A thoracic–abdominal CT scan revealed multiple pulmonary, hepatic and splenic nodules as well as enlarged mesenteric lymph nodes. Semiquantitative polymerase chain reaction demonstrated a high viral load in the blood (1000–2000 Eqv genome/105 cells). A fine-needle biopsy was taken of a hepatic nodule and a splenic nodule (3×2×2 cm) was resected. Following the diagnosis of EBV-associated SMT, the immunosuppressive therapy was reduced to prednisone, and the child was treated with chemotherapy (temozolomide 8 mg/kg per day on 5 days every month). He died after 2 months with seizures and coma. No autopsy was performed.
Materials and methods
Formalin-fixed tissue was sectioned (4 μm) and stained with haematoxylin–eosin–saffron. The immunohistochemical procedure used a panel of antibodies recognising relevant markers, such as vimentin, smooth muscle actin, desmin, CD31, CD34, S100 protein, Ki-67 and EBV latent membrane protein (LMP-1) (Dako, Glostrup, Denmark). Positive staining was visualised using peroxidase conjugates (EnVision+ system, Dako). EBV-encoded early RNAs (EBERs 1 and 2) were detected using in situ hybridisation with biotin-conjugated oligonucleotides (Kreatech, Amsterdam, The Netherlands).
Results
Macroscopically, the splenic nodule was encapsulated, firm and white. Microscopic examinations of biopsies taken from the liver and spleen demonstrated interlacing bundles of spindle cells with moderate cellularity in combination with some loosely textured myxoid areas of low cellularity. Tumour cells displayed eosinophilic cytoplasm and vesicular nuclei. The nuclei were elongated to cigar-shaped and slightly variable in size (Fig. 2). Mitotic figures were very scarce, and there was no haemorrhage or necrosis. Immunohistochemical staining and analysis demonstrated diffuse staining for vimentin and smooth muscle actin. Nuclear staining for Ki-67 was demonstrated in 10% of tumour cells. The results for desmin, CD31, CD34, S100 protein and LMP-1 were negative. The nucleus of most tumour cells expressed EBERs (Fig. 3).
Discussion
Patients who have undergone organ transplantation require lifelong immunosuppressive therapy. The incidence of various proliferative disorders, including SMT and susceptibility to EBV are increased in immunosuppressed patients. EBV is a DNA herpes virus that is able to immortalise infected cells. It is commonly found in adults, primarily infecting B-lymphocytes and capable of persisting indefinitely in a latent form. Infected B-cells may undergo chromosomal rearrangement and become hyperproliferative. T-lymphocytes normally constitute the major pool of proliferating cells associated with the host’s response to EBV infection [19]. Latent EBV infection is associated with a number of lymphoid, epithelial and mesenchymal tumours. CD21, the B-cell receptor for EBV, is found on the cell surface of SMT in human immunodeficiency virus (HIV)-positive (strong immunostaining) and HIV-negative (weak immunostaining) children [16]. EBERs 1 and 2 are demonstrated using in situ hybridisation in latently infected cells. Large amounts of EBV DNA and RNA have been demonstrated in SMT in immunocompromised patients [15, 16]. Monoclonal or biclonal EBV strains have been identified in SMT found both in patients following organ transplantation [14, 15] and in children with AIDS [10, 16]. Such EBV monoclonality suggests a primary role of the virus in oncogenesis of this tumour [4]. An EBV-associated liver tumour that had occurred after kidney transplantation in a 10-year-old patient presented a phenotypical spectrum, ranging from SMT to inflammatory pseudotumour, with genomic rearrangement of the ALK loci and co-localisation of the viral DNA and the ALK sequences [7]. EBV-associated SMT following organ transplantation may occur concurrently or sequentially with post-transplant lymphoproliferative disorders (PTLD), which often regress after reduction of immunosuppression. EBV-associated SMT and PTLD occur after similar tumour-free periods post-transplantation, exhibit EBV type-III latency, involve either donor or recipient tissues, are of clonal or multiclonal origin and display a wide spectrum of histological grade and clinical behaviour [19].
EBV-associated SMT following organ transplantation have been reported in 14 children (including the subject of this report) [2, 5, 6, 8, 11, 15, 18, 21, 24, 25, 26, 30] and 5 adults [1, 14, 23, 27, 29]: 10 males, 9 females, aged 18 days to 49 years at transplantation (mean 12.9 years and median 5.1 years). A variety of organs have been transplanted in the subjects of these studies, most often the liver (eight patients), kidney, or heart. The delay between the transplantation and the occurrence of SMT ranged from 1 year to 6 years (mean 3.6 years and median 3.8 years), with a single SMT measuring up to 15 cm [6] or, more often, multifocal or multicentric lesions in multiple organs or tissues. The most common locations of SMT were the liver (12 patients), originating from the donor or recipient, lung (from the donor in one patient), heart and colon (native in one patient) (Table 1). SMT was found in the intracranial, epidural area in a 5-year-old girl following heart transplantation. Immunosuppression was reduced, and the epidural mass was stable 3.5 years after biopsy [5]. The child reported in this study represents the only patient with brain tumour. In 12 of the patients described in the literature, the diagnosis was SMT of uncertain malignant potential. A further seven patients were diagnosed with leiomyosarcoma (well-differentiated in three patients, poorly differentiated in one patient). The malignant potential of these tumours is difficult to assess, and the diagnosis of SMT of uncertain malignant potential might be preferred instead of leiomyosarcoma or leiomyoma. The biological significance of criteria, such as tumour size, cellularity, atypia and mitotic counts probably differs according to the location of such tumours, with some apparently benign tumours proving to be lethal. The tumours did prove to be fatal in most patients, with death most often being a result of sepsis (four patients) or haemorrhage. Five of the seven patients who survived (at a 10-month to 12-year follow-up) have been treated by surgical resection (Table 1). In the case reported here, the brain tumour was lethal, despite the reduction of immunosuppression and the use of chemotherapy with good diffusion through the blood–brain barrier.
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The authors thank Paulo Gomes for his skilful technical help.
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Boudjemaa, S., Boman, F., Guigonis, V. et al. Brain involvement in multicentric Epstein–Barr virus-associated smooth muscle tumours in a child after kidney transplantation. Virchows Arch 444, 387–391 (2004). https://doi.org/10.1007/s00428-004-0975-7
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DOI: https://doi.org/10.1007/s00428-004-0975-7